A number of procedures for stabilizing substances prone to hydrolysis are described in the literature. These procedures can be summarized and grouped in the following manner:
1. Removal of water from the formulation
This operation primarily involves the spray-drying of solutions or suspensions of active substances and excipients or other drying processes which are applied either to the finished product or during preparation.
2. Coating of the active substances
The conventional processes here are micro-encapsulation or the spraying of polymers onto active substances in a suitable apparatus.
3. Rendering the active substances hydrophobic
These procedures range from simple mixing of the active substances with hydrophobic excipients to embedding of the active substances in waxy or fatty substances in a melt.
4. Achieving an optimum pH value
This simple method of minimizing the rate of hydrolysis, which is the normal method used for solutions, has seldom been described for use with solid pharmaceuticals. More often, it is generally proposed to add acidicly or basicly reacting excipients without direct adjustment of the pH.
The procedures mentioned above have various disadvantages, some of which are mentioned hereinafter. For example, the procedures of Group 1 not only subject the active substances to heat but also have the disadvantage that all the process steps following the drying operation, such as the packing, must be carried out under conditions of low humidity, since dry material can generally re-absorb water from the air in a very short time. Thus, these processes make the manufacture more expensive and are technically very complex.
The procedures of Group 2 are also cost-intensive. Furthermore, it is frequently essential to work with organic solvents, which means that precautions have to be taken to prevent environmental pollution and explosions.
The procedures of Group 3 often lead to a worsening of the release of active substance from the pharmaceutical preparation. The effect on the bio-pharmaceutical activity must be investigated for each individual case and is normally highly dependent upon the active substance.
The adjustment of the pH mentioned for Group 4 can only be controlled by means of the solution or suspension of the solid form. Local differences in pH in the solid pharmaceutical form must be included in the calculations.